A Note from William H. Andrews, Ph.D. President and CEO

Exciting Progress at Sierra Sciences

It's been just a little over two years since Sierra Sciences discovered our first telomerase-inducing drug, C0057684. That discovery took place on November 6, 2007. And, for two years, we've been scratching our heads, wondering: why haven't we found anything better? This month, that finally changed. Our investment in medicinal chemistry has begun to pay dividends, and on February 8, 2010, another landmark day in Sierra Sciences' history, we discovered that four of our custom-designed compounds were unambiguously stronger than C0057684. The best of these, C0313741, is twice as potent and no more toxic to human cells. We've reproduced that experiment several times since February 8, and we're now comfortable announcing it. For two years, we've been saying that our best compound induced telomerase at 6% of our goal; this month, we're upgrading that number to 12%.

Some of you have been e-mailing us and asking what we mean by "percent of goal," so I'll take a moment to explain that. When we talk about our "goal," we're referring to the level of teloemrase expressed in a HeLa cell. HeLa cells are cancer cells cultivated from a woman named Henrietta Lakcs in 1951. A very interesting book on Henrietta Lacks and her cells was published just this month: for more information, see: http://www.amazon.com/Immortal-Life-Henrietta-Lacks/dp/1400052173.

These cells are immortal, and they're the most thoroughly studied immortal cells in history. For the last six decades, they've exhibited no signs of aging whatsoever. Their telomeres are very short and never lengthen, but they also never shorten. For this reason, we hypothesize that the level of telomerase expressed in a HeLa cell is probably very close to the level of teloemrase a cell would have to express to achieve immortality. And adding C0313741 to a normal human cell, which ordinarily does not express telomerase, causes that cell to express 12% as much teloemrase as HeLa.

A follow-up question I'm often asked is "So, if that compound could be made completely non-toxic, does that mean it would reduce the rate of human aging by 12%?" The answer is: Possibly. That's what we hope. But for now, all I can say is: I don't know. No one knows. But we're looking forward to finding out!

Of course, when we do find a compound that induces telomerase at 100% of the level of HeLa, that doesn't mean our work ends there. HeLa is by no means a theoretical maximum for teloemrase; many cell lines express telomerase atmuch higher levels. So, stopping telomere shortening is only the first step. After that, we want to find a way to express teloemrase at a level that will actually lengthen our telomeres and, hopefully, make us younger.

It's exciting to have discovered a compound twice as potent as C0057684, which, just three weeks ago, was the strongest telomerase inducer the planet had ever seen. But even more exciting is the information our chemists have obtained from these results: we now know more about how to increase the potency of a telomerase activator than anyone has ever known before.

Federico Gaeta, our consultant in medicinal chemistry and drug development, puts it best. When one of our employees recently remakred that they were impressed by our progress this month, Federico smiled and replied, "You aint' seen nothing yet. And you can quote me on that."

William H. Andrews
Pesident and CEO, Sierra Sciences LLC

Sierra Sciences has a Facebook page that we use to keep our supporters up to date on the progress of our company. If you have a Facebook profile, you can receive these updates by "becoming a fan" of the company. Just visit this address and click "Become a Fan":http://www.facebook.com/pages/Sierra-Sciences/130839216671?ref=nf. Hope to see you there!

Sierra Sciences maintains a Twitter page where we post updates on our research, and the research of our colleagues in anti-aging science, in real time. Come follow us at http://twitter.com/SierraSci!

At our YouTube page, you can watch Dr. Andrews' presentations at last year's A4M conference in San Jose, and at the Manhattan Beach project last November. Be sure to subscribe to our channel so you don't miss upcoming videos! The channel can be found at http://www.youtube.com/sierrasciencesLLC.

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SIERRA SCIENCES NEWS

On February 3, BBC Horizon aired a one-hour special on the search for a cure for aging, entitled "Don't Grow Old." The episode featured Dr. Andrews, his father Ralph Andrews, and Sierra Sciences.

Dont' Grow Old attracted 1.74 million viewers on its premiere night, not including those watching in HD, in catch-up television, or on the Internet. It was a privelege to be able to broadcast our mission and our findings to such a wide audience.

Those of you living in the UK should be able to view the episode at http://www. bbc.co.uk/iplayer/episode/b00qm7zr/Horizon_20092010-_Dont_Grow_Old/. When the episode is made available to the rest of the world, we'll let you know!

On May 14, Dr. Andrews will be speaking in Key Largo, Florida on the effects of endurance exercise on telomere length. Several publications have recently shown that people who do intense endurance sports have longer telomeres than sedentary people.

The following day, Dr. Andrews will participate in the Keys 100 mile race form Key Largo to Key West. For more information on the race, go to http://www.keys100.com.

On Thursday, March 18, Dr. Andrews will be giving a talk entitled "Telomeres and Aging" at the ECOPRAM conference in Milan, Italy.

ECOPRAM is the European Conference on Preventive, Regenerative and Anti-Aging Medicine. It's a sister organization to A4m, the American Academy of Anti-Aging Medicine.

In the past, Dr. Andrews' talks at these conferences have been very well received. He's looking forward to the opportunity to present our research to a European audience.

Terry Carter, our Facilities Technician, passed away on February 21, 2010, from pancreatic cancer.

Terry has been an important part of Sierra Sciences for the last six years. When he first started working here, he was one of the first people hired to our operations department, and helped get the department up and running. Terry organized our laboratories, kept our scientists supplied with materials, maintained our machinery, and prepared plates for many of our experiments. He worked alongside everyone here at Sierra Sciences. He will be sorely missed by all of us.

ANTI-AGING NEWS

Many of you probably saw the press release two weeks ago about aging done at Newcastle University. This study, "Feedback between p21 and reactive oxygen production is necessary for cell senescence" http://www.ncbi.nlm.nih.gov/pubmed/2016060708), published online by Molecular Systems Biology on February 16, 2010, has become one of the most highly-publicized papers on aging that we've seen in a while.

The study shows for the first time that free radical production plays a role in inducing senescence apart from its role in causing telomere shortening. That is, senescence; whether or not it is induced by short telomeres, stress, or oncogenes; is initiated by the DNA Damage Response (already known) and this induces free radical production (not known before) through DNA Damage Response induced mitochondrial dysfunction. The free radical production in turn helps maintain the DNA Damage Reponse (i.e. a feedback loop). And, all this maintains senescence-related proliferation arrest.

The press release that everyone has read regarding this excellent publication may have been a bit misleading. The authors have not discovered THE "secret of aging," and the publication never "plays down the role of telomeres" as the press releases indicate. The paper, in fact, did a very good job of discussing telomeres in their rightful place as one of the sources of the DNA Damage Response that leads to senescence.

The press releases also state that the "breakthrough means that we stand a very much better chance of making a successful attack on age-related diseases while at the same time avoiding the risk of unwanted side-effects like cancer [from lenghtening telomeres??]". the authors didn't say anything in their paper that suggests that "interventions against individual components of the senescence phenotype (e.g. ROS production)" will not increase the risk of cancer in cells with short telomeres. They also didn't do anything to show that these interventions will decrease the rate of chromosomal rearrangements and mutations induced by short telomeres (which can lead to cancer). They also didn't suggests anything about what would happen to a cell if the telomeres got shorter than the length that induces senescence. Or, can the cell even survive or be healthy with that much telomere missing? But, in defense of the authors, these weren't the purposes of the paper. Nevertheless, we still don't know if lengthening telomeres is more likely to increase the risk of cancer or decrease the risk of cancer. We think it is great that the authors found a new target to relieve senescence related aging diseases, but it wasn't their goal to show that telomere shortening doesn't still need to be prevented. And, they didn't.

The press releases also state that "the telomere story has over-promised and the biology is more complicated". What is it that people believe that the telomere story has promised??? Definitely, this paper didn't discredit the well published and reproducible fact that if we keep telomeres long the DNA Damage Response and free radical production leading to senescence never occurs. Response and free radical production leading to senescence never occurs. So that promise still holds true. But, no one ever said that we know how the long telomeres do this. We're sure that however they do so, the system is very complicated; we promise!

We'll leave you with a quote from Thomas von Vglinicki, an author of this paper, with which we couldn't agree more: "It is absolutely essential to tread carefully in trying to alter processes that cause cells to age, because the last thing we want it to help age-damaged cells from breaking out to become malignant!"